Heat-Killed Bifidobacterium longum ZFML0012 Alleviates Rheumatoid Arthritis via Gut-Joint Axis Regulation: Remodeling Microbiota, Boosting SCFAs/L-Glutamine, and Rebalancing Th17/Treg Immunity.

Rheumatoid arthritis (RA) is an autoimmune disease closely associated with gut microbiota dysbiosis. Amid growing interest in microbial-derived therapeutics, postbiotics, defined as preparations of nonliving microorganisms and/or their components conferring host benefits, have emerged as candidates. However, the immunomodulatory potential of Bifidobacteria postbiotics in RA remains unexplored. This study investigated the effects of heat‑killed Bifidobacterium longum ZFML0012 (HK‑B. longum) on RA and its underlying mechanisms using in vitro and in vivo models. In LPS-induced cells, HK-B. longum significantly suppressed the expression of pro-inflammatory cytokines such as IL-1β and TNF-α while promoting the anti-inflammatory factor IL-10. In collagen-induced arthritis (CIA) mice, it reduced arthritis scores, joint swelling, and bone erosion. Mechanistically, HK-B. longum remodeled gut microbiota, increased SCFAs (acetate and butyrate), and particularly upregulated the immunomodulatory metabolite L-Glutamine in both gut and serum. In vitro experiments confirmed that L-Glutamine inhibited TNF‑α‑induced inflammation, abnormal proliferation, and migration in MH7A synovial cells. Meanwhile, HK‑B. longum regulated the T helper cell 17/Regulatory T cell (Th17/Treg) immune imbalance, modulated local inflammatory factors, and restored the osteoprotegerin/receptor activator of nuclear factor‑κB ligand (OPG/RANKL) ratio in joints. These findings provide new evidence for using postbiotics to alleviate RA through gut-joint axis regulation.